Familial hypercholesterolaemia: the Cape Town experience

Familial hypercholesterolaemia (FH), an autosomal dominantly inherited disorder characterised by elevated plasma low-density lipoprotein (LDL) cholesterol levels, tendon xanthomata and premature ischaemic heart disease, is amenable to treatment with modern medication. The clinical and biochemical details of 1 031 patients with FH were analysed. FH is the most common monogenic disorder of lipoprotein metabolism presenting to the Lipid Clinic at Groote Schuur Hospital, accounting for about 20% of consultations. The hospital classified 55% of the FH patients as white, 43% as coloured, 1.5% as Asian and 0.5% as black. In the FH cohort (whose mean age at presentation was 44 years), 80% had tendon xanthomata, 36% had arcus cornealis, and 14% had xanthelasma. Tendon xanthomata was present in almost 90% of patients by the age of 50 years. Arcus cornealis was present in about 45% by the age of 40 years, further increasing in frequency with age. Cardiovascular complications included ischaemic heart disease (43%), stroke (1.5%), transient ischaemic attacks (1.3%), and peripheral vascular disease (3.7%). The mean age of death was 55 (+13) years; 51 (+10) years in men and 61 (+12) years in women. In 46% of the cohort, a defective gene was identified by testing for locally prevalent mutations

SALT Spectropolarimetry and Self-Consistent SED and Polarization Modeling of Blazars

We report on recent results from a target-of-opportunity program to obtain spectropolarimetry observations with the Southern African Large Telescope (SALT) on flaring gamma-ray blazars. SALT spectropolarimetry and contemporaneous multi-wavelength spectral energy distribution (SED) data are being modelled self-consistently with a leptonic single-zone model. Such modeling provides an accurate estimate of the degree of order of the magnetic field in the emission region and the thermal contributions (from the host galaxy and the accretion disk) to the SED, thus putting strong constraints on the physical parameters of the gamma-ray emitting region. For the specific case of the $\gamma$-ray blazar 4C+01.02, we demonstrate that the combined SED and spectropolarimetry modeling constrains the mass of the central black hole in this blazar to $M_{\rm BH} \sim 10^9 \, M_{\odot}$.Comment: Submitted to Galaxies - Proceedings of "Polarized Emission from Astrophysical Jets", Ierapetra, Crete, June 12 - 16, 201

Familial Hypercholesterolaemia: The Cape Town Experience

Familial hypercholesterolaemia (FH), an autosomal dominantly inherited disorder characterised by elevated plasma LDL cholesterol levels, tendon xanthomata and premature ischaemic heart is amenable to treatment with modern medication. There is a paucity of clinical information on FH in South Africa. The clinical and biochemical details of 1031 patients who attended the lipid clinic at Groote Schuur Hospital with this diagnosis have been analysed. FH is the commonest monogenic disorder of lipoprotein metabolism presenting to the Lipid Clinic at Groote Schuur Hospital, accounting for about 20% of consultations. The hospital classified 55% of the FH patients as White, 43% as Coloured, 1.5% as Asian and 0.5% as Black. In the FH cohort, whose mean age at presentation was 44 years, 80% had tendon xanthomata, 36% had arcus cornealis and 14% had xanthelasma. Tendon xanthomata were present in almost 90% of patients by the age of 50 years. Arcus cornealis was present in about 45% by the age of 40 years, increasing further with age. Cardiovascular complications included ischaemic heart disease (43%), stroke (1.5%), transient ischaemic attacks (1.3%) and peripheral vascular disease (3.7%). The mean age of death was 55 (±13) years; 51 (±10) years in men and 61 (±12) years in women. In 46% of the cohort a defective gene was identified by testing for locally prevalent mutations. FH is a common, serious disease that can be diagnosed by clinical manifestations and routine laboratory tests at primary healthcare level. FH affects all ethnic groups in South Africa Effective treatment is available to prevent early and debilitating coronary disease but requires recognition and referral

Simvastatin enhances protection against Listeria monocytogenes infection in mice by counteracting Listeria-induced phagosomal escape

Statins are well-known cholesterol lowering drugs targeting HMG-CoA-reductase, reducing the risk of coronary disorders and hypercholesterolemia. Statins are also involved in immunomodulation, which might influence the outcome of bacterial infection. Hence, a possible effect of statin treatment on Listeriosis was explored in mice. Statin treatment prior to subsequent L. monocytogenes infection strikingly reduced bacterial burden in liver and spleen (up to 100-fold) and reduced histopathological lesions. Statin-treatment in infected macrophages resulted in increased IL-12p40 and TNF-α and up to 4-fold reduced bacterial burden within 6 hours post infection, demonstrating a direct effect of statins on limiting bacterial growth in macrophages. Bacterial uptake was normal investigated in microbeads and GFP-expressing Listeria experiments by confocal microscopy. However, intracellular membrane-bound cholesterol level was decreased, as analyzed by cholesterol-dependent filipin staining and cellular lipid extraction. Mevalonate supplementation restored statin-inhibited cholesterol biosynthesis and reverted bacterial growth in Listeria monocytogenes but not in listeriolysin O (LLO)-deficient Listeria . Together, these results suggest that statin pretreatment increases protection against L. monocytogenes infection by reducing membrane cholesterol in macrophages and thereby preventing effectivity of the cholesterol-dependent LLO-mediated phagosomal escape of bacteria

Decreased production of low density lipoprotein by atorvastatin after apheresis in homozygous familial hypercholesterolemia

Apheresis only partially controls raised low density lipoprotein cholesterol levels in patients with homozygous familial hypercholesterolemia, who usually respond poorly to lipid-lowering drugs. The efficacy and mechanism of action of a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, atorvastatin, was therefore investigated in seven homozygotes undergoing apheresis. One receptor-negative and six receptor-defective homozygotes undergoing plasma exchange or LDL apheresis every 2 weeks were studied during 2 months each on placebo and on atorvastatin 80 mg daily. Changes in plasma lipids and mevalonic acid, an index of cholesterol synthesis, were measured and the kinetics of the rebound of low density lipoprotein cholesterol and apolipoprotein B after apheresis were analyzed. All subjects had significant improvements on atorvastatin. Mean decreases in low density lipoprotein cholesterol were 31% greater both pre- and post-apheresis on atorvastatin compared with placebo, accompanied by a 63% decrease in mevalonic acid. Percentage changes in low density lipoprotein cholesterol and mevalonic acid were closely correlated (r = 0.89, P = 0.007). The mean production rates of low density lipoprotein cholesterol and apolipoprotein B were 21% and 25% lower, respectively, on atorvastatin than on placebo (P < 0.005 and <0.02) but changes in mean fractional clearance rates were not statistically significant. We conclude that atorvastatin enhances the efficacy of plasma exchange and low density lipoprotein apheresis in patients who lack low density lipoprotein receptors. This effect appears to be due to marked inhibition of cholesterol synthesis which results in a decreased rate of production of low density lipoprotein

Evaluation of the WRF and CHIMERE models for the simulation of PM₂.₅ in large East African urban conurbations

Urban conurbations of East Africa are affected by harmful levels of air pollution. The paucity of local air quality networks and the absence of the capacity to forecast air quality make difficult to quantify the real level of air pollution in this area. The CHIMERE chemistry transport model has been used along with the Weather Research and Forecasting (WRF) meteorological model to run high-spatial-resolution (2 × 2 km) simulations of hourly concentrations of particulate matter with an aerodynamic diameter smaller than 2.5 µm (PM2.5) for three East African urban conurbations: Addis Ababa in Ethiopia, Nairobi in Kenya, and Kampala in Uganda. Two existing emission inventories were combined to test the performance of CHIMERE as an air quality model for a target monthly period in 2017, and the results were compared against observed data from urban, roadside, and rural sites. The results show that the model is able to reproduce hourly and daily temporal variabilities in aerosol concentrations that are close to observed values from urban, roadside, and rural environments. CHIMERE's performance as a tool for managing air quality was also assessed. The analysis demonstrated that, despite the absence of high-resolution data and up-to-date biogenic and anthropogenic emissions, the model was able to reproduce 66 %–99 % of the daily PM2.5 exceedances above the World Health Organization (WHO) 24 h mean PM2.5 guideline (25 µg m−3) in the three cities. An analysis of the 24 h average PM2.5 levels was also carried out for 17 constituencies in the vicinity of Nairobi. This showed that 47 % of the constituencies in the area exhibited a poor Air Quality Index for PM2.5 that was in the unhealthy category for human health, thereby exposing between 10 000 and 30 000 people per square kilometre to harmful levels of air contamination

Effect of cranberry (Vaccinium macrocarpon) oligosaccharides on the formation of advanced glycation end-products

Background: The formation and accumulation of advanced glycation end-products (AGEs) are implicated in several chronic human illnesses including type-2 diabetes, renal failure, and neurodegenerative diseases. The cranberry (Vaccinium macrocarpon) fruit has been previously reported to show anti-AGEs effects, attributed primarily to its phenolic constituents. However, there is lack of similar data on the non-phenolic constituents found in the cranberry fruit, in particular, its carbohydrate constituents. Herein, a chemically characterized oligosaccharide-enriched fraction purified from the cranberry fruit was evaluated for its potential anti-AGEs and free radical scavenging effects. Objective: The aim of this study was to evaluate the in vitro anti-AGEs and free radical scavenging effects of a chemically characterized oligosaccharide-enriched fraction purified from the North American cranberry (Vaccinium macrocarpon) fruit. Method: The cranberry oligosaccharide-enriched fraction was purified from cranberry hull powder and characterized based on spectroscopic and spectrometric (NMR, MALDI-TOF-MS, and HPAEC-PAD) data. The oligosaccharide-enriched fraction was evaluated for its anti-AGEs and free radical scavenging effects by the bovine serum albumin-fructose, and DPPH assays, respectively. Results: Fractionation of cranberry hull material yielded an oligosaccharide-enriched fraction named Cranf1b-CL. The 1H NMR and MALDI-TOF-MS revealed that Cranf1b-CL consists of oligosaccharides ranging primarily from 6-mers to 9-mers. The monosaccharide composition of Cranf1b-CL was arabinose (25%), galactose (5%), glucose (47%) and xylose (23%). In the bovine serum albumin-fructose assay, Cranf1b-CL inhibited AGEs formation in a concentration-dependent manner with comparable activity to the synthetic antiglycating agent, aminoguanidine, used as the positive control (57 vs. 75%; both at 500μg/mL). In the DPPH free radical scavenging assay, Cranf1b-CL showed superior activity to the synthetic commercial antioxidant, butylated hydroxytoluene, used as the positive control (IC50 = 680 vs. 2200μg/mL, respectively). Conclusion: The in vitro anti-AGEs and free radical scavenging effects of cranberry oligosaccharides support previous data suggesting that these constituents may also contribute to biological effects of the whole fruit beyond its phenolic constituents alone. Also, this is the first study to evaluate a chemically characterized oligosaccharide fraction purified from the North American cranberry fruit for anti-AGEs and free radical scavenging properties